Classical steroid hormone action is mediated through intracellular steroid hormone receptors. These proteins dimerize, after steroid binding, translocate to the nucleus, and exert specific nuclear transcription factor effects on specific steroid-sensitive genes [1]. In recent years, however, a number of studies indicate that, in addition to the above genomic action, steroids bear non-genomic effects, mediated in minutes, and implicating different pathways than those involved in classical steroid receptor action [2, 3]. Non-genomic steroid actions were, in addition, been found in cells not expressing classical steroid receptors. The above, non-genomic steroid receptor actions were attributed to another class of steroid receptors, found on membrane of cells, and being biochemically, immunologically and pharmacologically different from classical steroid receptors. Until now, non-genomic steroid effects were found for estradiol, cortisoI, and testosterone, in animal tissues, usually not expressing classical receptors [2-13]. Activation of these non-classical steroid sites, found on membranes of cells was the increase of the flux of extracellular calcium to the cytosol [8-10, 12, 14], and in some times, modifications of the cytoskeleton [7, 15]. In all cases, BSA-conjugated steroids were used as ligands for these extracellular (membrane) steroid sites, in order to identify these sites. Indeed, covalent binding of steroids with high (60 kD) molecular weight proteins makes these molecules to loose their lipid solubility (and therefore the property of translocating to the cell through the plasma membrane) and confines them with water solubility and the possibility of binding to specific steroid sites. Commercially available sources of these compounds are currently available (e,g, Sigma Chemical Co. St Louis, Mo., USA). Nevertheless, human applications of this membrane steroid receptor activation have not been described so far.
GB 2 068 973 A, disclose conjugates of a steroid and an immunogenic protein such as human serum albumin for use in compositions for increasing ovulation in cattle.
EP 1 104 677 A2 discloses conjugates of a protein and a low molecular weight compound, where steroids are mentioned as examples of such. Bovine serum albumin is mentioned as an example of a protein useable in such conjugates. If at least part of the low molecular compounds is cytostaticum and the protein is a tumor specific antibody, an enzyme or a lectin the conjugates may be used for treatment of cancer.
U.S. Pat. No. 6,372,712 B1 discloses synthetic bifunctional molecules containing a drug moiety and a presenter protein ligand. Steroids are mentioned as examples of a drug moiety and albumin is mentioned as a preferred example of a presenter protein. The conjugates may be used to enhance the binding affinity and/or specificity of the agent to its target. It is stated that the conjugates can be used for treatment of different diseases dependent on the type of drug moiety used, but there are no specific teachings on which diseases may be treated with which drug moiety.
WO 01/82910 A2 discloses therapy of cancer using a composition comprising progesterone and RU486 (Mifesterone) or derivatives thereof and a portion of HPV E2 protein for the treatment of cervical cancer or certain pre-cancerous cervical lesions. The HPV E2 protein is known to be lethal for the cervical tissue and the connection with the steroid seems to enhance this effect. The steroid may be bound to a steroid carrier protein such as human serum albumin.
U.S. Pat. No. 4,215,102 A1 discloses a conjugate consisting of progesterone or estrogen, protein and a fluorochrome. The conjugates may be used for detection of steroid hormone receptors in excised human tissue sections.
WO 99/13914 A1 disclose the pharmaceutical compositions comprising therapeutic active substances having low aqueous solubility bound to a plasma protein fraction in controlled aggregation state in order to increase the soluble amount of the active substances and thereby increase the availability thereof.
WO 93/02691 A1 disclose a delivering system for glucocorticoids using a protein carrier molecule having a binding site for glucocorticoids and a binding site for the targeted cell population. There is not indicated particular indication for which pharmaceutical compositions comprising said delivering systems are useful but it may be used for conditions known to be treatable with glucocorticoids.